The overall goal of the proposed studies is to define the mechanisms by which environmental signals such as LPS influence the immunopathologic host response elements in the early stages of infection. Macrophages are now well recognized as key effector cells in the overall host responses to both infectious microbes and malignant cells. They play a pivotal role not only as antigen presenting cells in the development of a specific immunologic response to microbial protein antigens, but also as participants in the initial innate host inflammatory response to an infectious nidus. These inflammatory responses include the production of a substantial array of mediator molecules and proteins, making macrophage an extraordinary diverse cell in terms of spectrum of host responses which it is capable of making under specified conditions of infection. Our laboratory was among the first to establish concept that stimulus-specific macrophage desensitization and priming are differential aspects of the more general phenomenon of "reprogramming". The date have been recently generated to show a primary autocrine/paracrine role for LPS- induced IL-I 0, IL-12, and IFN-7 in the primary reprogramming events, although the exact pathway(s) by which regulation occurs, or whether additional cytokines are involved, have yet to be established. The proposed studies have been designed to define which macrophages intracellular signaling mechanisms contribute to selective activation pathways utilized by LPS; to establish the relative contribution of IL-I 0, IL-12, and IFN- gamma in autocrine/paracrine regulation of the macrophage potential for inflammatory mediator production and to evaluate whether reprogramming of macrophages contribute significantly to the development of T cell specific immune responses in the defense against pathogenic microorganisms. Identification of the experimental approaches for generation of macrophage-derived APC with distinct antigen-presenting capacity to regulate early polarization of either Th1 or Th2 subsets will provide a strong experimental basis for the eventual use of such immunotherapeutic approaches for potential modulation of the protective immune responses in appropriate infectious diseases in human.